Method and packaging for pressurized containers

ABSTRACT

A method for maintaining the enclosed volume of a sealed package at about ambient pressure, wherein the package contains a pressurized container comprising a drug, and an HFA (hydrofluoroalkane) propellant selected from the group consisting of HFA 134a and HFA p227, or a mixture thereof; wherein the method comprises the steps of (1) positioning an effective amount of a HFA adsorbent material, and said pressurized container, within a sealable package; (2) sealing the package so that the pressurized container and adsorbent are in an enclosed volume within the package at a pressure equal to about ambient pressure; and (3) adsorbing any leakage of the HFA propellant into the HFA adsorbent material so as to maintain the enclosed volume at about ambient pressure.

This application is continuation application of U.S. application Ser.No. 10/603,214, filed Jun. 25, 2003, which in turn claims priority toU.S. Provisional Application Ser. No. 60/394,421, filed Jul. 8, 2002,and to Great Britain Application Number 0214667.8, filed Jun. 26, 2002.

FIELD OF THE INVENTION

This invention relates to a method and a package for packagingpressurized containers suitable for relatively long-term storage. Moreparticularly, it relates to a package and packaging method that utilizesan HFA adsorbent material, such as a molecular sieve, to absorb oradsorb propellant gases gradually leaked out from a pressurizedcontainers, whereby preventing the propellant gas from inflating thepackage.

BACKGROUND OF THE INVENTION

Pressurized containers such as inhalers may need to be packed inimpermeable packages to prevent atmospheric moisture ingress. The use ofsuch impermeable packages can cause accumulation of propellant gasesthat gradually leak from the pressurized container and may eventuallylead to failure of the seals of the package. This problem becomes moreprominent when traditional propellants chlorofluorocarbons (CFCs) arereplaced by hydrofluoroalkane propellants (such as HFA-134a and HFA-227)for environmental reasons.

U.S. Pat. Nos. 6,179,118 B1, 6,119,853 and 6,352,152 address thisproblem by using a flexible package that is “impermeable to moisture andpermeable to the propellant.” While this appears to be a good approach,applicants had much difficulty in fabricating a flexible wrappingmaterial which is impermeable to moisture and permeable to thepropellant so that the resulting package would operate similar to “avirtual one-way valve”. Presumably, fabricating such flexible wrappingmaterials is much more technically involved and more costly than itappears from reading the aforementioned patents. Therefore, there is aneed for a simpler and more understandable way to solve the inflationproblem in packing pressurized containers.

Furthermore, the ability of the packages disclosed in U.S. Pat. Nos.6,179,118 B1, 6,119,853 and 6,352,152, to prevent gas build up in thepackages, would appear to be limited by the permeability of the wrappingmaterial to the propellant and the rate at which the propellant isreleased from the container.

Therefore, there is a need for an enhanced drug product comprising apackage that is impermeable, or substantially impermeable, to the egressof HFA gas from within the package, and still is capable of maintainingthe enclosed volume of the is sealed package at about ambient pressurewhen any leakage of HFA gas propellant occurs.

SUMMARY OF THE INVENTION

A primary object of the present invention is to provide a new packagefor pressurized inhalers, which will reduce or eliminate the inflationproblems normally associated with conventional packaging methods.Another object of the present invention is to provide simpler method forsolving the inflation problem than the prior art approaches. Anotherobject of the present invention is to provide a new package forpressurized inhalers, which will reduce or eliminate the egress of HFAgas propellant from within the package, normally associated withconventional packaging methods. A further object of the presentinvention is to provide a method for maintaining the enclosed volume ofa sealed package at about ambient pressure, wherein the package containsleakage from a pressurized container comprising an HFA(hydrofluoroalkane) propellant.

It is believed that the mechanism by which the HFA adsorbent materialprevents package from inflating is by entrapping the propellant gasesgradually leaked from the pressurized container.

The various features of novelty which characterize the invention arepointed out with particularity in the claims annexed to and forming apart of this disclosure. For a better understanding of the invention,its operating advantages, and specific objects attained by its use,reference should be made to the drawings and the following descriptionin which there are illustrated, and described, preferred embodiments ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph summarizing a study that shows that the molecularsieve is an effective HFA adsorbent for entrapping a propellant gas fromthe air, whereby preventing inflation of the package.

FIG. 2 shows the rate of moisture absorption by the molecular sievesduring the first hour of exposure to the atmosphere.

FIG. 3 shows the rate of moister absorption by the same molecular sievesused in FIG. 2 during an exposure period of 12 hours.

FIGS. 4 and 5 shows that the molecular sieves' capacity for adsorbingpropellant gases is reduced if the sieves are pre-exposed to moisturefor different time intervals.

FIG. 6 depicts a typical metered dose (pressurized container) inhalerpackage according to the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) In a first embodiment, the invention provides, a method formaintaining the enclosed volume of a sealed package at about ambientpressure, wherein the package contains a pressurized MDI (metered doseinhaler) container comprising a drug, and an HFA (hydrofluoroalkane)propellant selected from the group consisting of HFA 134a and HFA p227,or a mixture thereof; wherein the method comprises the steps of:

(i) positioning an effective amount of a HFA adsorbent material, andsaid pressurized container, within a sealable package;

(ii) sealing the package so that the pressurized container and adsorbentare in an enclosed volume within the package at a pressure equal toabout ambient pressure; and

(iii) adsorbing any leakage of the HFA propellant into the HFA adsorbentmaterial so as to maintain the enclosed volume at about ambientpressure.

(2) In another embodiment, the invention provides a method according toembodiment (1), wherein the drug is selected from the group consistingof bronchodilators, antihistamines, lung surfactants, antiviral agents,corticosteroids, ant-inflammatory agents, anti-cholinergics, andantibacterial agents.

(3) In another embodiment, the invention provides method according toembodiment (1) or (2), wherein the pressurized MDI (metered doseinhaler) container further comprises one or more excipients selectedfrom the group consisting of surfactants, preservatives, flavorings,antioxidants, anti-aggregating agents and co-solvents.

(4) In another embodiment, the invention provides a method according toany one of embodiments (1) to (3), wherein the HFA propellant is HFA134a.

(5) In another embodiment, the invention provides a method according toany one of embodiments (1) to (3), wherein the HFA propellant is HFAp227.

(6) In another embodiment, the invention provides a method according toany one of embodiments (1) to (5), wherein the HFA adsorbent material iscapable of adsorbing the HFA propellant up to about 25% of the weight ofthe adsorbent.

(7) In another embodiment, the invention provides a method according toany one of embodiments (1) to (5), wherein the HFA gas adsorbentmaterial is capable of adsorbing the HFA propellant up about 20% of theweight of the adsorbent.

(8) In another embodiment, the invention provides a method according toany one of embodiments (1) to (7), wherein the HFA adsorbent materialcomprises material selected from the group consisting of molecularsieves, activated clays, activated alumina, silica, zeolites, bauxites,and mixtures thereof.

(9) In another embodiment, the invention provides a method according toembodiment (8), wherein the HFA adsorbent material is 10 Å (Angstrom)molecular sieves.

(10) In another embodiment, the invention provides a method according toembodiment (9), wherein the molecular sieves, in an amount of about 4grams, absorbs about 230 ml of HFA p227.

(11) In another embodiment, the invention provides a method according toembodiment (9), wherein the molecular sieves, in an amount of about 4grams, absorbs about 230 ml of HFA 134a.

(12) In another embodiment, the invention provides a method according toanyone of embodiments (1) to (11), wherein the package is impermeable toHFA 134a.

(13) In another embodiment, the invention provides a method according toanyone of embodiments (1) to (12), wherein the package is impermeable toHFA p227.

(14) In another embodiment, the invention provides a method according toanyone of embodiments (1) to (12), wherein the package is permeable toHFA p227.

(15) In another embodiment, the invention provides a method according toembodiment (14), wherein the package has a permeability to HFA p227 thatis less than or equal to about 0.25 cc of HFA p227 per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(16) In another embodiment, the invention provides a method according toembodiment (14), wherein the package has a permeability to HFA p227 thatis less than or equal to about 0.15 cc of HFA p227 per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(17) In another embodiment, the invention provides a method according toembodiment (14), wherein the package has a permeability to HFA p227 thatis less than or equal to about 0.10 cc of HFA p227 per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(18) In another embodiment, the invention provides a method according toembodiment (14), wherein the package has a permeability to HFA p227 thatis less than or equal to about 0.05 cc of HFA p227 per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(19) In another embodiment, the invention provides a method according toany one of embodiments (1) to (11) or (14), wherein the package ispermeable to HFA 134a.

(20) In another embodiment, the invention provides a method according toembodiment (19), wherein the package has a permeability to HFA 134a thatis less than or equal to about 4.1 cc of HFA 134a per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(21) In another embodiment, the invention provides a method according toembodiment (19), wherein the package has a permeability to HFA 134a thatis less than or equal to about 3.5 cc of HFA 134a per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(22) In another embodiment, the invention provides a method according toembodiment (19), wherein the package has a permeability to HFA 134a thatis less than or equal to about 2.5 cc of HFA 134a per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(23) In another embodiment, the invention provides a method according toembodiment (19), wherein the package has a permeability to HFA 134a thatis less than or equal to about 1.5 cc of HFA 134a per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(24) In another embodiment, the invention provides a method according toembodiment (19), wherein the package has a permeability to HFA 134a thatis less than or equal to about 1.0 cc of HFA 134a per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(25) In another embodiment, the invention provides a method according toembodiment (19), wherein the package has a permeability to HFA 134a thatis less than or equal to about 0.5 cc of HFA 134a per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(26) In another embodiment, the invention provides a method according toany one of embodiments (1) to (25), wherein the package is made ofmetal, glass, or plastic, and is selected from the group consisting ofbottles, bags, drum boxes, and irregularly shaped containers.

(27) In another embodiment, the invention provides a method according toany one of embodiments (1) to (26), wherein the package is made ofplastic.

(28) In another embodiment, the invention provides a method according toembodiment (27) wherein the plastic is a flexible laminate having abarrier layer providing said package with permeability to HFA 134aand/or HFA p227.

(29) In another embodiment, the invention provides a method according toembodiment (27), wherein the plastic is a flexible laminate having abarrier layer providing said package with impermeability to HFA 134aand/or HFA p227.

(30) In another embodiment, the invention provides a method according toembodiment (28) or (29), wherein said flexible laminate has threelayers: polyester/aluminum/polyethylene, wherein the aluminum layer isbetween the polyester and polyethylene layers.

(31) In another embodiment, the invention provides a method according toembodiment (28) or (29), wherein said barrier layer is made of aluminumfoil.

(32) In another embodiment, the invention provides a method according toany one of embodiments (1) to (31), wherein the sealed package ishermetically sealed by heat-sealing, gluing, welding, brazing,mechanical closures or clamps, or compression.

(33) In another embodiment, the invention provides a use of an HFAadsorbent to maintain the pressure of an enclosed volume within a sealedpackage at about ambient pressure, wherein the sealed package comprises:

(i) a pressurized MDI (metered dose inhaler) container comprising adrug, a HFA (hydrofluoroalkane) propellant selected from the groupconsisting of HFA 134a and HFA p227, or a mixture thereof;

(ii) an effective amount of an HFA adsorbent material;

wherein the pressurized MDI container and HFA adsorbent material arewithin the enclosed volume of the sealed package.

(34) In another embodiment, the invention provides a use according toembodiment (33), wherein the drug is selected from the group consistingof bronchodilators, antihistamines, lung surfactants, antiviral agents,corticosteroids, ant-inflammatory agents, anti-cholinergics, andantibiotics.

(35) In another embodiment, the invention provides a use according toembodiment (33) or (34), wherein the pressurized MDI (metered doseinhaler) container further comprises one or more excipients selectedfrom the group consisting of surfactants, preservatives, flavorings,antioxidants, anti-aggregating agents and co-solvents.

(36) In another embodiment, the invention provides a use according toany one of embodiments (33) to (35), wherein the HFA propellant is HFA134a.

(37) In another embodiment, the invention provides a use according toany one of embodiments (33) to (35), wherein the HFA propellant is HFAp227.

(38) In another embodiment, the invention provides a use according toany one of embodiments (33) to (37), wherein the HFA adsorbent materialis capable of adsorbing the HFA propellant up to about 25% of the weightof the adsorbent.

(39) In another embodiment, the invention provides a use according toany one of embodiments (33) to (37), wherein the HFA gas adsorbentmaterial is capable of adsorbing the HFA propellant up about 20% of theweight of the adsorbent.

(40) In another embodiment, the invention provides a use according toany one of embodiments (33) to (39), wherein the HFA adsorbent materialcomprises material selected from the group consisting of molecularsieves, activated clays, activated alumina, silica, zeolites, bauxites,and mixtures thereof.

(41) In another embodiment, the invention provides a use according toembodiment (40) wherein the HFA adsorbent material is 10 Å (Angstrom)molecular sieves.

(42) In another embodiment, the invention provides a use according toembodiment (41), wherein the molecular sieves, in an amount of about 4grams, absorbs about 230 ml of HFA p227.

(43) In another embodiment, the invention provides a use according toembodiment (41), wherein the molecular sieves, in an amount of about 4grams, absorbs about 230 ml of HFA 134a.

(44) In another embodiment, the invention provides a use according toany one of embodiments (33) to (43), wherein the package is impermeableto HFA 134a.

(45) In another embodiment, the invention provides a use according toany one of embodiments (33) to (42), wherein the package is impermeableto HFA p227.

(46) In another embodiment, the invention provides a use according toany one of embodiments (33) to (42), wherein the package is permeable toHFA p227.

(47) In another embodiment, the invention provides a use according toembodiment (46), wherein the package has a permeability to HFA p227 thatis less than or equal to about 0.25 cc of HFA p227 per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(48) In another embodiment, the invention provides a use according toembodiment (46), wherein the package has a permeability to HFA p227 thatis less than or equal to about 0.15 cc of HFA p227 per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(49) In another embodiment, the invention provides a use according toembodiment (46), wherein the package has a permeability to HFA p227 thatis less than or equal to about 0.10 cc of HFA p227 per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(50) In another embodiment, the invention provides a use according toembodiment (46), wherein the package has a permeability to HFA p227 thatis less than or equal to about 0.05 cc of HFA p227 per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(51) In another embodiment, the invention provides a use according toanyone of embodiments (33) to (43), wherein the package is permeable toHFA 134a.

(52) In another embodiment, the invention provides a use according toembodiment (51), wherein the package has a permeability to HFA 134a thatis less than or equal to about 4.1 cc of HFA 134a per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(53) In another embodiment, the invention provides a use according toembodiment (51), wherein the package has a permeability to HFA 134a thatis less than or equal to about 3.5 cc of HFA 134a per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(54) In another embodiment, the invention provides a use according toembodiment (51), wherein the package has a permeability to HFA 134a thatis less than or equal to about 2.5 cc of HFA 134a per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(55) In another embodiment, the invention provides a use according toembodiment (51), wherein the package has a permeability to HFA 134a thatis less than or equal to about 1.5 cc of HFA 134a per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(56) In another embodiment, the invention provides a use according toembodiment (51), wherein the package has a permeability to HFA 134a thatis less than or equal to about 1.0 cc of HFA 134a per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(57) In another embodiment, the invention provides a use according toembodiment (51), wherein the package has a permeability to HFA 134a thatis less than or equal to about 0.5 cc of HFA 134a per square meter ofpackage per day at about 1 bar pressure and about room temperature.

(58) In another embodiment, the invention provides a use according toany one of embodiments (33) to (57), wherein the package is made ofmetal, glass, or plastic, and is selected from the group consisting ofbottles, bags, drum boxes, and irregularly shaped containers.

(59) In another embodiment, the invention provides a use according toembodiment (58), wherein the package is made of plastic.

(60) In another embodiment, the invention provides a use according toembodiment (59), wherein the plastic is a flexible laminate having abarrier layer providing said package with impermeability to HFA 134aand/or HFA p227.

(61) In another embodiment, the invention provides a use according toembodiment (59) or (60), wherein the plastic is a flexible laminatehaving a barrier layer providing said package with permeability to HFA134a and/or HFA p227.

(62) In another embodiment, the invention provides a use according toembodiment (60) or (61), wherein said flexible laminate has threelayers: polyester/aluminum/polyethylene, wherein the aluminum layer isbetween the polyester and polyethylene layers.

(63) In another embodiment, the invention provides a use according toembodiment (60) or (61), wherein said barrier layer is made of aluminumfoil.

(64) In another embodiment, the invention provides a use according toany one of embodiments (33) to (63), wherein the sealed package ishermetically sealed by heat-sealing, gluing, welding, brazing,mechanical closures or clamps, or compression.

(65) In another embodiment, the invention provides a pharmaceuticalproduct comprising:

(i) a pressurized MDI (metered dose inhaler) container comprising adrug, and an HFA (hydrofluoroalkane) propellant selected from the groupconsisting of HFA 134a and HFA p227, or a mixture thereof;

(ii) an effective amount of an HFA adsorbent material; and

(iii) a sealed package having an enclosed volume within which thepressurized container and the HFA adsorbent material are situated,

wherein the sealed package is impermeable to the HFA propellant and thepressure within the enclosed volume of the package is equal to aboutambient pressure; and

wherein the HFA adsorbent material is capable of adsorbing the HFApropellant so as to maintain a constant pressure within said enclosedvolume, when any leakage of the HFA propellant occurs from thepressurized container.

(66) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (65), wherein the drug is selected fromthe group consisting of bronchodilators, antihistamines, lungsurfactants, antiviral agents, corticosteroids, ant-inflammatory agents,anti-cholinergics, and antibiotics.

(67) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (65) or (66), wherein the pressurizedMDI (metered dose inhaler) container further comprises one or moreexcipients selected from the group consisting of surfactants,preservatives, flavorings, antioxidants, anti-aggregating agents andco-solvents.

(68) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (65) to (67), wherein theHFA propellant is HFA 134a.

(69) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (65) to (67), wherein theHFA propellant is HFA p227.

(70) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (65) to (69), wherein theHFA adsorbent material is capable of adsorbing the HFA propellant up toabout 25% of the weight of the adsorbent.

(71) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (65) to (69), wherein theHFA gas adsorbent material is capable of adsorbing the HFA propellant upabout 20% of the weight of the adsorbent.

(72) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (65) to (71), wherein theHFA adsorbent material comprises material selected from the groupconsisting of molecular sieves, activated clays, activated alumina,silica, zeolites, bauxites, and mixtures thereof.

(73) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (72), wherein the HFA adsorbent materialis 10 Å (Angstrom) molecular sieves.

(74) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (73), wherein the molecular sieves, inan amount of about 4 grams, absorbs about 230 ml of HFA p227.

(75) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (73), wherein the molecular sieves, inan amount of about 4 grams, absorbs about 230 ml of HFA 134a.

(76) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (65) to (75), wherein thepackage is impermeable to HFA 134a.

(77) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (65) to (76), wherein thepackage is impermeable to HFA p227.

(78) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (65) to (77), wherein thepackage is made of metal, glass, or plastic, and is selected from thegroup consisting of bottles, bags, drum boxes, and irregularly shapedcontainers.

(79) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (71), wherein the package is made ofplastic.

(80) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (79), wherein the plastic is a flexiblelaminate having a barrier layer providing said package withimpermeability to HFA 134a and/or HFA p227.

(81) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (80), wherein said flexible laminate hasthree layers: polyester/aluminum/polyethylene, wherein the aluminumlayer is between the polyester and polyethylene layers.

(82) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (80), wherein said barrier layer is madeof aluminum foil.

(83) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (65) to (82), wherein thesealed package is hermetically sealed by heat-sealing, gluing, welding,brazing, mechanical closures or clamps, or compression.

(84) A pharmaceutical product comprising:

(i) a pressurized MDI (metered dose inhaler) container comprising adrug, and an HFA (hydrofluoroalkane) propellant selected from the groupconsisting of HFA 134a and HFA p227, or a mixture thereof;

(ii) an effective amount of an HFA adsorbent material; and

(iii) a sealed package having an enclosed volume within which thepressurized container and the HFA adsorbent material are situated,

wherein the pressure within the enclosed volume of the package is equalto about ambient pressure;

wherein the HFA adsorbent material is capable of adsorbing the HFApropellant so as to maintain a constant pressure within said enclosedvolume, when any leakage of the HFA propellant occurs from thepressurized container; and

wherein the package has a permeability to HFA p227 that is less than orequal to about 0.25 cc of HFA p227 per square meter of package per dayat about 1 bar pressure and about room temperature, or a permeability toHFA 134a that is less than or equal to about 4.1 cc of HFA 134a persquare meter of package per day at about 1 bar pressure and about roomtemperature.

(85) A pharmaceutical product according to embodiment (84), wherein thepackage has a permeability to HFA p227 that is less than or equal toabout 0.15 cc of HFA p227 per square meter of package per day at about 1bar pressure and about room temperature.

(86) A pharmaceutical product according to embodiment (84), wherein thepackage has a permeability to HFA p227 that is less than or equal toabout 0.10 cc of HFA p227 per square meter of package per day at about 1bar pressure and about room temperature.

(87) A pharmaceutical product according to embodiment (84), wherein thepackage has a permeability to HFA p227 that is less than or equal toabout 0.05 cc of HFA p227 per square meter of package per day at about 1bar pressure and about room temperature.

(88) A pharmaceutical product according to embodiment (84), wherein thepackage has a permeability to HFA 134a that is less than or equal toabout 3.5 cc of HFA 134a per square meter of package per day at about 1bar pressure and about room temperature.

(89) A pharmaceutical product according to embodiment (84), wherein thepackage has a permeability to HFA 134a that is less than or equal toabout 2.5 cc of HFA 134a per square meter of package per day at about 1bar pressure and about room temperature.

(90) A pharmaceutical product according to embodiment (84), wherein thepackage has a permeability to HFA 134a that is less than or equal toabout 1.5 cc of HFA 134a per square meter of package per day at about 1bar pressure and about room temperature.

(91) A pharmaceutical product according to embodiment (84), wherein thepackage has a permeability to HFA 134a that is less than or equal toabout 1.0 cc of HFA 134a per square meter of package per day at about 1bar pressure and about room temperature.

(92) A pharmaceutical product according to embodiment (84), wherein thepackage has a permeability to HFA 134a that is less than or equal toabout 0.5 cc of HFA 134a per square meter of package per day at about 1bar pressure and about room temperature.

(93) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (84) to (92), wherein thedrug is selected from the group consisting of bronchodilators,antihistamines, lung surfactants, antiviral agents, corticosteroids,ant-inflammatory agents, anti-cholinergics, and antibiotics.

(94) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (84) to (93), wherein thepressurized MDI (metered dose inhaler) container further comprises oneor more excipients selected from the group consisting of surfactants,preservatives, flavorings, antioxidants, anti-aggregating agents andco-solvents.

(95) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (84) to (94), wherein theHFA propellant is HFA 134a.

(96) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (84) to (94), wherein theHFA propellant is HFA p227.

(97) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (84) to (96), wherein theHFA adsorbent material is capable of adsorbing the HFA propellant up toabout 25% of the weight of the adsorbent.

(98) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (84) to (96), wherein theHFA gas adsorbent material is capable of adsorbing the HFA propellant upabout 20% of the weight of the adsorbent.

(99) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (84) to (98), wherein theHFA adsorbent material comprises material selected from the groupconsisting of molecular sieves, activated clays, activated alumina,silica, zeolites, bauxites, and mixtures thereof.

(100) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (99), wherein the HFA adsorbent materialis 10 Å (Angstrom) molecular sieves.

(101) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (100), wherein the molecular sieves, inan amount of about 4 grams, absorbs about 230 ml of HFA p227.

(102) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (100), wherein the molecular sieves, inan amount of about 4 grams, absorbs about 230 ml of HFA 134a.

(103) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (84) to (102), wherein thepackage is made of metal, glass, or plastic, and is selected from thegroup consisting of bottles, bags, drum boxes, and irregularly shapedcontainers.

(104) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (103), wherein the package is made ofplastic.

(105) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (104), wherein the plastic is a flexiblelaminate having a barrier layer providing said package with permeabilityto HFA 134a and/or HFA p227.

(106) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (105), wherein said flexible laminatehas three layers: polyester/aluminum/polyethylene, wherein the aluminumlayer is between the polyester and polyethylene layers.

(107) In another embodiment, the invention provides a pharmaceuticalproduct according to embodiment (105), wherein said barrier layer ismade of aluminum foil.

(108) In another embodiment, the invention provides a pharmaceuticalproduct according to any one of embodiments (84) to (107), wherein thesealed package is hermetically sealed by heat-sealing, gluing, welding,brazing, mechanical closures or clamps, or compression.

(109) In another embodiment, the invention provides a flexible laminateaccording to any one of embodiments (30), (62), (81), and (106)comprising 12 micron polyester/9 micron aluminum foil/50 micronpolyethylene.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Also, various featuresof the invention which are, for brevity, described in the context of asingle embodiment, may also be provided separately or in any suitablesubcombination.

The Ability of HFA Adsorbents to Entrap Propellants

It is discovered that HFA adsorbent materials, especially molecularsieves, are capable of removing (by entrapping) propellant gases fromlocal environment. The present invention takes advantage of thisproperty of the HFA adsorbent materials and enclose them in animpermeable, or substantially impermeable, flexible package as a meansto preventing the leaked out propellant from inflating the package. Byenclosing one or more HFA adsorbent materials in the package to absorbor adsorb any leaked-out propellant, applicants can make the flexiblewrapping material as impermeable as possible to prevent moisture ingresswithout worrying about the leaked-out propellant inflating and causingfailure of the seals in the flexible package. To determine the propertype and amount of HFA adsorbent material to be used in each package fora pressurized inhaler containing a specific propellant, applicantsconducted the following measurement and determined that about 4 grams ofa sachet of 10 Angstrom molecular sieves can remove (adsorb)approximately 230 ml of HFA-227 propellant.

Two methods are used to measure the absorption capability of the sieves.The Initial Measurement method uses flowrap packs containing activeproduct to obtain an approximate data on the amount of propellant thatwould be absorbed. The Precise Measurement method builds on the resultsobtained from the Initial Measurement method but uses containers filledonly with propellant for the purpose of eliminating any possible effectfrom the active compounds (i.e., medicaments).

For the Initial Measurement method, a number of sample packs (flexiblepackage enclosing a pressurized inhaler containing HFA-227 propellantand the molecular sieve to be tested) are obtained and checked for sealintegrity by testing on the Qualitek leak tester. The packs wereorientated with the valve of the pressurized inhaler on the top. Withminimum disturbance, the orientation of the packs is reversed (with thevalve pointing downwards) and the aerosol fired for a predeterminednumber of shots and the time taken to deflate each of the packs wasrecorded. The reason for these precautions is to minimize active productexpelled with propellant, which may coat the sieves and possibly reducetheir absorption capacity. The packs are then opened and the sieves areexamined for the presence of the active product on their surfaces. Thepresence of the active product would indicate that inverting has notprevented the active product from being expelled and consequently itcould have effected the absorption rate. The results of the InitialMeasurement are as follows:

All packs with up to 15 shots fired return to original size within 10minutes, while packs with 20 shorts fired show slight inflation after 15minutes. Examination of the sieves used showed evidence of productdeposition on the inside of the pouch and on the outside of theadsorbent sachet although none could be seen on the surface of theadsorbent itself. As such this was considered a good guide to theadsorbent capacity prior to the more precise method being undertaken.

For the Precise Measurement method, the following steps are followed:

-   1. A number of pressurized inhalers (aerosol cans) filled only with    HFA-227 Propellant are obtained. They are numbered and their weights    are recorded.-   2. A number of flexible packages with a open end are obtained. They    are also numbered.-   3. Each aerosol can in turn is placed into an actuator and inserted    into the flexible package.-   4. A predetermined amount of molecular sieves is transferred from an    unused polyethylene bag to a smaller minigrip bag. Using tweezers to    avoid transfer of moisture, the sieves are weighed and inserted into    each of the packages in turn.-   5. Each of the packages, now containing an aerosol can and molecular    sieves, is immediately heat sealed using a AstraPack Heatsealer that    has been set up to produce effective seals with this particular    package material. This step is repeated for all the packages.-   6. The first five packages remain as sealed. This is for the purpose    of assessing the effect of moisture pickup from the actuator and/or    the air in the package, which can serve as the base line for all    other measurements.-   7. The remaining packages are divided into sets of five. The cans of    a set are fired for a predetermined number of shots. The maximum    number of shorts is determined based on the information obtained    from the Initial Measurement method. Sets with more than 10 shots    are given time to deflate before continuing with the next shot. All    the sets of packages are stored for a minimum of 24 hours to allow    the maximum propellant absorption to occur.-   8. The packages are then leak tested using a Qualitek leak tester to    ensure all packages have been adequately sealed and hence the data    obtained are relevant. Results from packages failing the leak test    are discarded.-   9. Each package is opened in turn and the sieve and the can are    re-weighed. The sieve is weighed first to avoid weight increase due    to atmospheric moisture absorption.-   10. The weight loss from each can and the weight gain of the sieve    are obtained and the average for each set is calculated. The data    are then plotted on a graph to show the rate of weight gain by the    sieves and the number of shots (and hence the volume of gas)    required to reach maximum absorption level. Similarly, the data on    the average weight loss from the cans are plotted to show the    equivalent transfer of propellant from the cans into the sieves    until final absorption for sieves reached (see FIG. 1).

As shown in FIG. 1, comparison of weight gain by the molecular sieveagainst gas volume indicates a steady rise in weight until about 25shots (equate to 230 ml) of propellant has been absorbed. This ismatched by the weight loss from the cans climbed while the weight of thesieves remained steady. Thus, it is concluded that about a 4 gramssachet of a 10 Angstrom molecular sieve can remove (adsorb)approximately 230 ml of HFA-227 propellant.

Of course, the HFA adsorbent material's capacity to absorb thepropellant may vary under actual production line conditions because theHFA adsorbent material may be pre-exposed to the atmosphere for acertain period of time and absorb atmospheric moisture. Absorption ofmoisture limits the eventual capacity of the HFA adsorbent material toabsorb propellant gases. Therefore, it should be taken intoconsideration in practicing the present invention. In the specificembodiment disclosed herein, applicants first determine the rate atwhich an HFA adsorbent material absorbs atmospheric moisture underconditions close to actual production line conditions (see FIGS. 2 and3), then examine the effect of the length of atmospheric exposure on theeventual capacity of propellant adsorption under typical productionconditions (see FIGS. 4 and 5). The data from this study are used todetermine a time allowance for normal production processes, whilst stillalways ensuring that the original targeted amount of propellant can beadsorbed.

As indicated in FIGS. 2 and 3, the moisture absorption during the firsthour of exposure can reach 20% of the maximum moisture absorption at 20°C./45% RH (relative humility) and 34% at 25° C./60% RH. Applicants alsoexamined the difference in moisture absorption between the sieves in topand bottom positions of a bulk container found that molecular sievesdirectly exposed to the atmosphere will absorb moisture much morerapidly than those protected by virtue of being in a lower position inthe container. This supports the view that sieves in a reel format willmaintain their effectiveness longer. These data will help determineproper procedures of handling molecular sieves in the productionenvironment.

In FIGS. 4 and 5, the molecular sieves are exposed to the productionconditions for the prescribed period of time and then immediatelypackaged using an Astrapack heatsealer. The resulting packs are left for10 minutes to allow the seals to cool and then the aerosols (filled withpropellant only) are actuated 5 times so that the packages expend. Thepacks are left for another 10 minutes to allow to adsorb the propellant.The actuating procedure is repeated until each sieve reached its maximumadsorption capacity. At the end of a 24-hour period (a period to ensuremaximum adsorption of the propellant), each pack is opened and thesieves are weighed immediately. FIG. 4 shows that the amount (in grams)of propellant adsorbed by 4 grams of the molecular sieves is reducedfollowing exposure to moisture for the different time periods indicated.FIG. 5 shows the percentage propellant adsorption per gram of molecularsieves over the same time periods as in FIG. 4. The goal in thisparticular case is to adsorb 100 ml of HFA-227 propellant (equivalent to0.76 g) by using a pouch containing 4 grams of molecular sieves. Thedata showing in FIGS. 4 and 5 indicate this goal can be achieved even ifthe sieves are exposed to the normal atmospheric moisture in theproduction line for 30 minutes.

The above study results demonstrate that inclusion of an HFA adsorbentinside the impermeable, or substantially impermeable, package is asimple, practical and effective solution to the inflation problem ofpackages for pressurized containers. Particularly, molecular sieves arevery effective HFA adsorbent materials against package inflation whenused in practicing the present invention.

Although there are various types of HFA adsorbent materials availableand their effectiveness against any given propellant may varyconsiderably, it is understood that people of ordinary skill in the artcan easily adopt some conventional assay methods, such as theabove-described study, to determine the type and amount of HFA adsorbentmaterial that is effective in reducing package inflation caused by aparticular propellant leaked from the pressurized container enclosed inthe package.

The Propellants

Propellants for use in the invention mean pharmacologically inertliquids with boiling points from about room temperature (25° C.) toabout −25° C. which singly or in combination exert a high vapor pressureat room temperature. Upon activation of the MDI system, the high vaporpressure of the propellant in the MDI forces a metered amount of drugformulation out through the metering valve then the propellant veryrapidly vaporizes dispersing the drug particles. The propellants used inthe present invention are preferably hydrofluorocarbons orhydrofluoroalkanes such as HFA-134a and HFA-227.

Drugs

The term “drug” as used herein is intended to encompass the presentlyavailable pharmaceutically active drugs used therapeutically and furtherencompasses future developed therapeutically effective drugs that can beadministered by the intrapulmonary route. Drugs may be selected from,for example, analgesics, e.g. codeine, dihydromorphine, ergotamine,fentanyl or morphine, anginal preparations, e.g. diltiazem;antiallergics, e.g. cromoglycate, ketotifen or nedocromil;antiinfectives e.g. cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines pentamidine, and Neuraminidase Inhibitors,such as zanamivir (Relenza®) available from GlaxoSmithkline; andRibavirin (Virazole®) manufactured by ICN Pharmaceuticals, Inc.;antihistamines, e.g. mnethapyfilene; antitussives, e.g. noscapine;beta-adrenergics that include bronchodilators such as salbutamol,salmeterol, ephedrine, adrenaline, fenoterol, forinoterol, isoprenaline,phenylephrine, phenylpropanolamine, reproterol, rimiterol, terbutaline,isoetharine, tulobuterol, orciprenaline, or(−)4-amino-3,5-dichloro-.alpha.-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol,epinephrine (Primatene), formoterol (Foradil), isoproterenol (Isuprel),isoetharine (Bronkosol), metaproterenol (Alupent, Metaprel), albuterol(Proventil, Ventolin), terbutaline (Bricanyl, Brethine), bitolterol(Tornalate), pirbuterol (Maxair), salmeterol (Serevent),salmeterol+fluticasone combination (Advair Diskus), andalbuterol+atrovent combination (Combivent); sodium channel blockers suchas amiloride, anticholinergics e.g. ipratropium, atropine or oxftropium;hormones, e.g. cortisone, hydrocordisone or prednisolone; andtherapeutic proteins and peptides, e.g. insulin or glucagon;anti-inflammatory drugs used in connection with the treatment ofrespiratory diseases include steroids such as NASACORT AQ®(triamcinolone acetonide), AZMACORT AQ® (triamcinolone acetonide)flunisolide, fluticasone, budesonide, triamcinolone acetonide,beclomethasone (Vanceril, Beclovent), budesonide (Pulmicort)dexamethasone, flunisolide (Aerobid), fluticasone (Flovent),salmeterol+fluticasone combination (Advair Diskus), and triamcinolone(Azmacort), and Mediator-release inhibitors such as Intal® (cromolynsodium), and nedocromil sodium (Tilade); leukotrine (LT) inhibitors,vasoactive intestinal peptide (VIP), tachykinin antagonists, bradykininantagonists, endothelin antagonists, heparin furosemide, anti-adhesionmolecules, cytokine modulators, biologically active endonucleases,recombinant human (rh) DNase compounds, alpha-antitrypsin and disodiumcromoglycate (DSCG); and lung surfactants such as lipid-containingcompositions as described in TONGE et. Al, WO 99/09955; Pulmonarysurfactants as decribed in Devendra et. Al, Respir Res 2002, 3:19;Infasurf® available from ONY; Curosurf® available from Dey Laboratories;Exosurf® by Glaxo Wellcome; Survanta available from Abbot; Surfaxin®lung surfactant available from Discovery Laboratories.

The present invention is intended to encompass the free acids, freebases, salts, amines and various hydrate forms including semi-hydrateforms of such drugs and is particularly directed towardspharmaceutically acceptable formulations of such drugs which areformulated in combination with pharmaceutically acceptable excipientmaterials generally known to those skilled in the art, preferablywithout other additives such as preservatives.

Preferred drug formulations do not include additional components such aspreservatives which have a significant effect on the overallformulation. Thus preferred formulations consist essentially ofpharmaceutically active drug and a pharmaceutically acceptable carrier(e.g., water and/or ethanol). However, if a drug is liquid without anexcipient the formulation may consist essentially of the drug which hasa sufficiently low viscosity that it can be aerosolized using adispenser of the present invention.

Drug Formulations

Drug formulations for use in the invention may be free or substantiallyfree of formulation excipients, e.g., surfactants and cosolvents, etc.Such drug formulations are advantageous since they may be substantiallytasteless and odorless, less irritant and less toxic thanexcipient-containing formulations. Thus, a preferred drug formulationconsists essentially of a drug, or a physiologically acceptable salt orsolvate thereof, optionally in combination with one or more otherpharmacologically active agent, and a hydrofluorocarbon propellant.

Optionally, the aerosol formulations according to the invention mayfurther comprise one or more cosolvent. A polar cosolvent such as C₂₋₆aliphatic alcohols and polyols, e.g., glycerol, ethanol, isopropanol andpropylene glycol, preferably ethanol, may be included in the drugformulation in the desired amount, either as the only excipient or inaddition to other excipients, such as surfactants. Suitably, the drugformulation may contain 0.01 to 5% w/w based on the propellant of apolar cosolvent, e.g., ethanol, preferably 0.1 to 5% w/w, e.g., about0.1 to 1% w/w.

Optionally, the aerosol formulations according to the invention mayfurther comprise one or more surfactants. The surfactants must bephysiologically acceptable upon administration by inhalation. Withinthis category are included surfactants such as oleic acid, sorbitantrioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene(20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate,natural lecithin, oleyl polyoxyethylene (2) ether, stearylpolyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, blockcopolymers of oxyethylene and oxypropylene, synthetic lecithin,diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate,isopropyl myristate, glyceryl monooleate, glyceyl monostearate, glycerylmonoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol400, cetyl pyridinium chloride, benzalkonium chloride, olive oil,glyceryl monolaurate, corn oil, cotton seed oil and sunflower seed oil.Preferred surfactants are lecithin, oleic acid and sorbitan trioleate.The amount of surfactant employed is desirably in the range of 0.0001%to 50% w/w ratio relative to the drug, in particular 0.05 to 5% w/wratio.

Optionally, the aerosol formulations according to the invention mayfurther comprise one or more stabilizers. The stabilizer is selectedfrom the group consisting of glycin, glycine, alanine, valine, leucine,isoleucine, methionine, threonine, isovaline, phenylalanine, tyrosine,serine, histidine, tryptophan, proline, hydroxyproline, arginine,ornithine, asparagine, citrulline, aspartic acid, cysteine, glutamicacid, glutamine, lysine, hydroxylysine, N-acetyl-L-cysteine,phenylalanine, trans-4-hydroxy-L-proline, tyrosine,L-aspartyl-L-phenylalanine methylester and a mixture of any of theforegoing.

Optionally, the aerosol formulations according to the invention mayfurther comprise one or more antioxidants. The antioxidant may beselected from the group consisting of tocopherol, deteroxime mesylate,methyl paraben, ethyl paraben and ascorbic acid and mixtures thereof. Apreferred antioxidant is tocopherol.

The Package

According to one embodiment of the present invention, shown in FIG. 6,the pharmaceutical product has an impermeable, or substantiallyimpermeable, flexible package 10, in which a metered dose pressurizedcontainer 20, inhalation device 30 and a molecular sieve 40 enclosed ina sachet 50, are sealed in an enclosed volume 60.

The flexible package is conventional and its manufacturing is wellwithin the knowledge of the people skilled in the art. In general, thepackage is constructed from flat reels of laminate which are folded orotherwise formed according to the packaging equipment technology into apackage by means of sealing and cutting. In this embodiment the packageis constructed from a flat reel of flexible material which is curledaround into a long tube and a seal 14 is formed by heating (welding) theedges of the tube together. The cross seals 12 are formed by a straightheater bar which clamps the laminate tube before and after the packagecontents (i.e., the inhaler and the adsorbent sachet). It also cuts thecontinuous tube into individual packs. As a result, there is a longcontinuous seal 14 down the middle of the pack and the cross seals 12 atboth ends.

Other package types may include more or less seals according to thedesired shape of the container, which may be flat seals or crimped, andmay include gussets. The seals may be formed by heating (welding) or bythe use of pressure sensitive materials. In a further embodiment theflexible laminates may be formed using heat, pressure and/or vacuum intoblisters or pockets to contain the product and which are then sealed byheating.

Although a flexible package is preferred, other types of enclosures orcontainers may be suitable, whether flexible or inflexible, providedthat the enclosure chosen is impermeable, or substantially impermeable,to moisture ingress. In general, when the package or enclosure isimpermeable, or substantially impermeable, to moisture, it is alsoimpermeable, or substantially impermeable, to the propellant thatgradually leaks out from the enclosed pressurized container. This maygradually build-up a pressure within the package or enclosure, which isundesirable. In this context, “substantially impermeable” to thepropellant means that the level of the propellant in the enclosed volumeof the package or enclosure will elevate if no measure, such asinclusion of an HFA adsorbent material, is taken to reduce it. Or inother words, the egress rate of the propellant gas allowed by thepackage or enclosure is lower than the rate by which it is leaked intothe enclosed volume of the package or enclosure from the pressurizedcontainer. Preferably, a substantially impermeable package of thepresent invention has a permeability to HFA p227 that is less than orequal to about 0.25 cc of HFA p227 per square meter of package per dayat about 1 bar pressure and about room temperature, or a permeability toHFA 134a that is less than or equal to about 4.1 cc of HFA 134a persquare meter of package per day at about 1 bar pressure and about roomtemperature. Also, in this context, “impermeable” to the propellantmeans impenetrable by the HFA propellant gas used in the invention.

Flexible Material for Making Packages

A preferred flexible material for making the package is a laminate,although other materials may also be satisfactorily employed. The mainlimitations are is that the package material must be substantiallyimpermeable to atmosphere moisture, and impermeable or substantiallyimpermeable, to the HFS propellant used.

The laminate used in making packages generally consists of severallayers of materials either co-extruded or bonded together to form anapparently single film of “laminate”. As an example, a suitable laminatemay have three layers adhesively laminated to each other: an innerlayer, a barrier layer and an outer layer. For example, Pharmaflex Ltd.,part of Alcan inc. (Cramlington, Northumberland, England) supplies alaminate film having three layers: 12 micron polyester/9 micron aluminumfoil/50 micron polyethylene (product catalog LMP-F BRI/72/H1). Also,another laminate that could be used in the invention comprises polyester(16.9 gsm/12 micron, orientated and acrylic coated)/low densitypolyethylene (20 gsm, coloured white using Titanium dioxide)/aluminiumfoil (24.3 gsm/9 micron)/polyethylene copolymer (5 gsm)/low densitypolyethylene (13 gsm)/linear low density polyethylene (37 gsm/40micron).

The inner layer is disposed on the inner surface of the package (i.e.the side in contact with the inhaler device) and is normally athermoplastic layer and heat-sealable. A common material for the innerlayer is polyethylene, but other polyolefinic or cyclo-olefinicmaterials may also be used. In addition, specialist materials such asionomers are also frequently used for making the inner layer, forexample, the ionomer under the tradename Surlyn. Properties whichdistinguish these ionomers resins from other polyolefin heat-sealedpolymers are high clarity, high impact resistance, low haze inlamination, tear resistance, abrasion resistance, solid state toughness,and moisture imperviousness.

The barrier layer is disposed between the inner and outer layers (i.e.it is sandwiched between the inner and outer layer) and providesimpermeability, or substantial impermeability, to the package. Aluminumfoil is commonly used for the barrier layer, although any other metalscapable of being rolled into thin sheets can also be satisfactorilyused. A typical thickness for the aluminum foil layer is about 8 or 9microns. Alternatively, the barrier layer may be metalized films, madeup of tin, iron, zinc, magnesium or other metals coated by vacuumdeposition or sputtering onto a polymeric sheet.

The outer layer is disposed on the surface of the barrier layer, on theopposite side to the inner layer. The outer layer normally providessupport, impact resistance, protection for the barrier layer and generalrobustness to the pack. A commonly used material for the outer layer ispolyester, although other material, such as paper, may also be used.

Adhesives may be used to join the respective layers of materialstogether. The adhesive layers are typically substantially smaller inthickness relative to the thickness of the substrate, heat sealableand/or protective layers which they bond.

The number, size, and shape of the layers are not limited to thoselayers shown in the drawings. Any number of layers with relative areasof any size and predetermined thickness may be used so long as theflexible package forms an enclosed volume which substantially preventsingression of water vapor and particulate matter into the enclosedvolume while being impermeable, or substantially impermeable to any HFAleakage from the MDI device. The size, shape, and number of layers ofthe package is typically a function of the size and contents of thepressurized container which includes a drug and HFA propellant.

Preferred exemplary thicknesses of the three layers include an outerlayer 1 to 40, preferably 4 to 30, more preferably 10 to 23 microns, andmost preferably 12 microns; a barrier layer of 1 to 100, preferably 3 to70, more preferably 5 to 50 microns, more preferably 6 to 20 microns andmost preferably 9 microns. For the inner layer, preferred exemplarythicknesses include thicknesses of 1 to 100, preferably 5 to 70, morepreferably 10 to 60, more preferably 20 to 55 microns, and mostpreferably 50 microns.

Preferred exemplary embodiments include a polyester film as the outerlayer having a thickness ranging from 12 to 23 microns. The polyesterfilm is laminated to an aluminum foil as the substrate layer having athickness ranging from 6 to 20 microns. The aluminum foil is laminatedto am inner film such as a polyethylene film having a thickness rangingfrom 20 to 50 microns.

Alternative preferred embodiments include aluminum metalized polyesterfilm laminated to an inner layer as outlined above. Another embodimentincludes a silicon oxide coplated polyester film laminated to an innerlayer as outlined above. Yet, in another embodiment, a polyester film asan outer layer having a thickness ranging from 12 to 30 microns islaminated to an aluminum foil substrate layer having a thickness rangingfrom 6 to 20 microns, the aluminum foil being laminated to a polyesterfilm of 12 to 30 microns which is laminated to an inner layer asoutlined above. In another embodiment, a polypropylene film as an outerlayer having a thickness ranging from 15 to 30 microns is laminated toan aluminum foil barrier layer having a thickness ranging from 6 to 20microns, and the aluminum foil is laminated to an inner layer asoutlined above. The laminates of the present invention can be adhesivelylaminated or extrusion laminated.

The laminate can be formed of any material described above and of anythickness as described above, as long as the final laminate isimpermeable, or substantially impermeable, to HFA 134a or HFA p227.

The permeability, or substantial impermeability, of the laminate may betested by a variety of techniques known to the skilled person. Forexample, three pieces of 75 mm diameter discs are die stamped fromlaminate material. The thickness of the laminate disc are then measuredand recorded. The samples are then placed into test chambers andvacuumed down to 23° C. for at least three hours. Once total vacuum hasstabilized approximately 50 psi of HFA p227 propellant is applied to thetop half of the disc sample, this being the outlet pressure for thecylinder at laboratory temperature, whist the bottom side is still undervacuum. A similar test can be carried out using 30 psi of HFA 134apropellant applied to the top half of the disc sample.

HFA Adsorbent and Gaseous Substances

“HFA adsorbent” means a substance which has the ability to condense orhold HFA molecules on its surface or in its inner structure, an activityoften referred as “adsorbing” or “absorbing”. Examples of HFA adsorbentsmaterial selected from the group consisting of molecular sieves,activated clays (including, montmorillonite and bentonite clay, andother known activated clays e.g. those clays supplied by Colin StewartMinchem Ltd, Cheshire, UK), activated alumina, silica, zeolites,bauxites, and mixtures thereof. Preferably, 10 Å (Angstrom) molecularsieves.

The present invention is not limited to any specific HFA adsorbents orspecific gaseous substances. Although there are many different HFAadsorbent, and there are various types of propellant gases, it isbelieved that any propellant gas can be in principle entrapped by aproperly-chosen HFA adsorbent. By following the information disclosedherein, it is well within the ordinary skill of the artisans in thefield to choose a proper HFA adsorbent for a given propellant gas.Practitioners can make an initial choice based on their knowledge andexperience (for example, weighing the factors such as the molecular sizeof the gaseous substance and the pore size of an HFA adsorbent as wellas electronic charges it carries) and then conduct tests (such as thosedisclosed herein or some other methods) to determine the actualeffectiveness of the chosen HFA adsorbent against a given propellantgas. They may need to repeat the process until a proper HFA adsorbent isfound.

As described in the foregoing, applicants have found that molecularsieves with a pore size of about 10 Angstroms is an effective HFAadsorbent material. Inclusion of about 4 grams of a sachet of themolecular sieve supplied by AtoFina (Solihull, England) under the tradename Siliporite, for example, is found sufficient per package to preventinflation. More detailed technical information about molecular sievesand their other industrial uses can be found in the Hajduarticle—-“Molecular Seives: Unique Moisture and Odor-Taste ControlMaterial”, D. Hajdu, T. J. Dangieri and S. R. Dunne, TAPPI Polym.,Laminations Coat. Conf. (1999), Vol. 2, p. 655-662, which isincorporated herein by reference.

The HFA Adsorbent Sachet

Although it is not necessary to have a sachet to contain the HFAadsorbent within the package, it is usually preferred. The HFA adsorbentsachets are commercially available from many suppliers includingSud-Chemie (Middlewich, England). The sachet, with a “tea-bag” likeappearance, is generally manufactured from synthetic fibers, such aspolyamide or polyester fibers or blends thereof. Commercially availablematerials suitable for making HFA adsorbent sachets include, forexample, GDT-II from San-ei Corporation (Osaka, Japan) and Tyvek fromPerfecseal (Londonderry N. Ireland U.K.). However, a suitable sachet maybe in other convenient shapes or appearances and made from otherpermeable materials. The molecular sieve material, contained within thesachet is commercially available from several manufacturers. For exampleAtoFina (Solihull, England) market a molecular sieve under the tradename of Siliporite.

The Pressurized Container

The pressurized container is preferably an MDI container. The term “MDI”or “metered dose inhaler” means a unit comprising a can and a drugmetering device. Exemplary pressurized containers for use in MDIs aredisclosed in WO 96/32151, WO 96/32345, WO 96/32150, WO 96/32099, andU.S. Pat. Nos. 6,293,279, 6,253,762, and 6,149,892.

Most often the MDI can and cap are made of aluminum or an alloy ofaluminum, although other metals not affected by the drug formulation,such as stainless steel, an alloy of copper or tin plate, may be used.An MDI can may also be fabricated from glass or plastic. Preferably,however, the MDI cans employed in the present invention are made ofaluminum or an alloy thereof. Advantageously, strengthened aluminum oraluminum alloy MDI cans may be employed. Such strengthened MDI cans arecapable of withstanding particularly stressful coating and curingconditions, e.g., particularly high temperatures, which may be requiredfor certain fluorocarbon polymers.

Strengthened MDI cans which have a reduced tendency to malform underhigh temperatures include MDI cans comprising side walls and a base ofincreased thickness and MDI cans comprising a substantially ellipsoidalbase (which increases the angle between the side walls and the base ofthe can), rather than the hemispherical base of standard MDI cans. MDIcans having an ellipsoidal base offer the further advantage offacilitating the coating process.

The MDI cans of the present invention include MDI cans supplied byPresspart of Blackburn, Lancashire, U.K., or by Neotechnic of Clitheroe,Lancashire U.K. The MDI cans typically have a neck diameter of 20millimeters, although any suitable neck diameter may be used and canvary in height from 30 millimeters to 60 millimeters.

While there have been described and pointed out fundamental novelfeatures of the invention as applied to a preferred embodiment thereof,it will be understood that various omissions and substitutions andchanges, in the form and details of the packages and methodsillustrated, may be made by those skilled in the art without departingfrom the spirit of the invention. For example, it is expressly intendedthat all combinations of those elements and/or method steps whichperform substantially the same function in substantially the same way toachieve the same results are within the scope of the invention.

The invention is not limited by the embodiments described above whichare presented as examples only but can be modified in various wayswithin the scope of protection defined by the appended patent claims.

1. A method for maintaining the enclosed volume of a sealed package atabout ambient pressure, wherein the package contains pressurized MDI(metered dose inhaler) container comprising a drug, and an HFA(hydrofluoroalkane) propellant selected from the group consisting of HFA134a and HFA p227, or a mixture thereof; wherein the method comprisesthe steps of: (i) positioning an effective amount of a HFA adsorbentmaterial, and said pressurized container, within a sealable package;(ii) sealing the package so that the pressurized container and adsorbentare in an enclosed volume within the package at a pressure equal toabout ambient pressure; and (iii) adsorbing any leakage of the HFApropellant into the HFA adsorbent material so as to maintain theenclosed volume at about ambient pressure.
 2. The method according toclaim 1, wherein the drug is selected from the group consisting ofbronchodilators, antihistamines, lung surfactants, antiviral agents,corticosteroids, ant-inflammatory agents, anti-cholinergics, andantibiotic.
 3. The method according to claim 1, wherein the pressurizedMDI (metered dose inhaler) container further comprises one or moreexcipients selected from the group consisting of surfactants,preservatives, flavorings, antioxidants, anti-aggregating agents andco-solvents.
 4. The method according to claim 1, wherein the HFApropellant is HFA 134a.
 5. The method according to claim 1, wherein theHFA propellant is HFA p227.
 6. The method according to claim 1, whereinthe HFA adsorbent material is capable of adsorbing the HFA propellant upto about 25% of the weight of the adsorbent.
 7. The method according toclaim 1, wherein the HFA gas adsorbent material is capable of adsorbingthe HFA propellant up to about 20% of the weight of the adsorbent. 8.The method according to claim 1, wherein the HFA adsorbent materialcomprises material selected from the group consisting of molecularsieves, activated clays, activated alumina, silica, zeolites, bauxites,and mixtures thereof.
 9. The method according to claim 1, wherein thepackage is permeable to HFA p227.
 10. The method according to claim 9,wherein the package has a permeability to HFA p227 that is less than orequal to about 0.25 cc of HFA p227 per square meter of package per dayat about 1 bar pressure and about room temperature.
 11. The methodaccording to claim 9, wherein the package has a permeability to HFA p227that is less than or equal to about 0.15 cc of HFA p227 per square meterof package per day at about 1 bar pressure and about room temperature.12. The method according to claim 9, wherein the package has apermeability to HFA p227 that is less than or equal to about 0.10 cc ofHFA p227 per square meter of package per day at about 1 bar pressure andabout room temperature.
 13. The method according to claim 9, wherein thepackage has a permeability to HFA p227 that is less than or equal toabout 0.05 cc of HFA p227 per square meter of package per day at about 1bar pressure and about room temperature.
 14. The method according toclaim 1, wherein the package is permeable to HFA 134a.
 15. The methodaccording to claim 14, wherein the package has a permeability to HFA134a that is less than or equal to about 4.1 cc of HFA 134a per squaremeter of package per day at about 1 bar pressure and about roomtemperature.
 16. The method according to claim 14, wherein the packagehas a permeability to HFA 134a that is less than or equal to about 3.5cc of HFA 134a per square meter of package per day at about 1 barpressure and about room temperature.
 17. The method according to claim14, wherein the package has a permeability to HFA 134a that is less thanor equal to about 2.5 cc of HFA 134a per square meter of package per dayat about 1 bar pressure and about room temperature.
 18. The methodaccording to claim 14, wherein the package has a permeability to HFA134a that is less than or equal to about 1.5 cc of HFA 134a per squaremeter of package per day at about 1 bar pressure and about roomtemperature.
 19. The method according to claim 14, wherein the packagehas a permeability to HFA 134a that is less than or equal to about 1.0cc of HFA 134a per square meter of package per day at about 1 barpressure and about room temperature.
 20. The method according to claim14, wherein the package has a permeability to HFA 134a that is less thanor equal to about 0.5 cc of HFA 134a per square meter of package per dayat about 1 bar pressure and about room temperature.
 21. The methodaccording to claim 1, wherein the package is made of metal, glass, orplastic, and is selected from the group consisting of bottles, bags,drum boxes, and irregularly shaped containers.
 22. The method accordingto claim 1, wherein the package is made of plastic.
 23. The methodaccording to claim 22, wherein the plastic is a flexible laminate havinga barrier layer providing said package with permeability to HFA 134aand/or HFA p227.
 24. The method according to claim 1, wherein the sealedpackage is hermetically sealed by heat-sealing, gluing, welding,brazing, mechanical closures or clamps, or compression.
 25. Use of anHFA adsorbent to maintain the pressure of an enclosed volume within asealed package at about ambient pressure, wherein the sealed packagecomprises: (i) a pressurized MDI (metered dose inhaler) containercomprising a drug, a HFA (hydrofluoroalkane) propellant selected fromthe group consisting of HFA 134a and HFA p227, or a mixture thereof;(ii) an effective amount of an HFA adsorbent material; wherein thepressurized MDI container and HFA adsorbent material are within theenclosed volume of the sealed package.
 26. The use according to claim25, wherein the drug is selected from the group consisting ofbronchodilators, antihistamines, lung surfactants, antiviral agentscorticosteroids, ant-inflammatory agents, anti-cholinergics, andantibiotics.
 27. The use according to claim 25, wherein the pressurizedMDI (metered dose inhaler) container further comprises one or moreexcipients selected from the group consisting of surfactants,preservatives, flavorings, antioxidants, anti-aggregating agents andco-solvents.
 28. The use according to claim 25, wherein the HFApropellant is HFA 134a.
 29. The use according to claim 25, wherein theHFA propellant is HFA p227.
 30. The use according to claim 25, whereinthe HFA adsorbent material is capable of adsorbing the HFA propellant upto about 25% of the weight of the adsorbent.
 31. The use according toclaim 25, wherein the HFA gas adsorbent material is capable of adsorbingthe HFA propellant up to about 20% of the weight of the adsorbent. 32.The use according to claim 25, wherein the HFA adsorbent materialcomprises material selected from the group consisting of molecularsieves, activated clays, activated alumina, silica, zeolites, bauxites,and mixtures thereof.
 33. The use according to claim 32, wherein the HFAadsorbent material is 10 Å (Angstrom) molecular sieves.
 34. The useaccording to claim 33, wherein the molecular sieves, in an amount ofabout 4 grams, absorbs about 230 ml of HFA p227.
 35. The use accordingto claim 33, wherein the molecular sieves, in an amount of about 4grams, absorbs about 230 ml of HFA 134a.
 36. The use according to claim25, wherein the package is impermeable to HFA 134a.
 37. The useaccording to claim 25, wherein the package is impermeable to HFA p227.38. The use according to claim 25, wherein the package is permeable toHFA p227.
 39. The use according to claim 38, wherein the package has apermeability to HFA p227 that is less than or equal to about 0.25 cc ofHFA p227 per square meter of package per day at about 1 bar pressure andabout room temperature.
 40. The use according to claim 38, wherein thepackage has a permeability to HFA p227 that is less than or equal toabout 0.15 cc of HFA p227 per square meter of package per day at about 1bar pressure and about room temperature.
 41. The use according to claim38, wherein the package has a permeability to HFA p227 that is less thanor equal to about 0.10 cc of HFA p227 per square meter of package perday at about 1 bar pressure and about room temperature.
 42. The useaccording to claim 38, wherein the package has a permeability to HFAp227 that is less than or equal to about 0.05 cc of HFA p227 per squaremeter of package per day at about 1 bar pressure and about roomtemperature.
 43. The use according to claim 25, wherein the package ispermeable to HFA 134a.
 44. The use according to claim 43, wherein thepackage has a permeability to HFA 134a that is less than or equal toabout 4.1 cc of HFA 134a per square meter of package per day at about 1bar pressure and about room temperature.
 45. The use according to claim43, wherein the package has a permeability to HFA 134a that is less thanor equal to about 3.5 cc of HFA 134a per square meter of package per dayat about 1 bar pressure and about room temperature.
 46. The useaccording to claim 43, wherein the package has a permeability to HFA134a that is less than or equal to about 2.5 cc of HFA 134a per squaremeter of package per day at about 1 bar pressure and about roomtemperature.
 47. The use according to claim 43, wherein the package hasa permeability to HFA 134a that is less than or equal to about 1.5 cc ofHFA 134a per square meter of package per day at about 1 bar pressure andabout room temperature.
 48. The use according to claim 43, wherein thepackage has a permeability to HFA 134a that is less than or equal toabout 1.0 cc of HFA 134a per square meter of package per day at about 1bar pressure and about room temperature.
 49. The use according to claim43, wherein the package has a permeability to HFA 134a that is less thanor equal to about 0.5 cc of HFA 134a per square meter of package per dayat about 1 bar pressure and about room temperature.
 50. The useaccording to claim 25, wherein the package is made of metal, glass, orplastic, and is selected from the group consisting of bottles, bags,drum boxes, and irregularly shaped containers.
 51. The use according toclaim 50, wherein the package is made of plastic.
 52. The use accordingto claim 51, wherein the plastic is a flexible laminate having a barrierlayer providing said package with impermeability to HFA 134a and/or HFAp227.
 53. The use according to claim 51, wherein the plastic is aflexible laminate having a barrier layer providing said package withpermeability to HFA 134a and/or HFA p227.
 54. The use according to claim52, wherein said flexible laminate has three layers:polyester/aluminum/polyethylene, wherein the aluminum layer is betweenthe polyester and polyethylene layers.
 55. The use according to claim52, wherein said barrier layer is made of aluminum foil.
 56. The useaccording to claim 25 wherein the sealed package is hermetically sealedby heat-sealing, gluing, welding, brazing, mechanical closures orclamps, or compression.
 57. A pharmaceutical product comprising: (i) apressurized MDI (metered dose inhaler) container comprising a drug, andan HFA (hydrofluoroalkane) propellant selected from the group consistingof HFA 134a and HFA p227, or a mixture thereof; (ii) an effective amountof an HFA adsorbent material; and (iii) a sealed package having anenclosed volume within which the pressurized container and the HFAadsorbent material are situated, wherein the pressure within theenclosed volume of the package is equal to about ambient pressure;wherein the HFA adsorbent material is capable of adsorbing the HFApropellant so as to maintain a constant pressure within said enclosedvolume, when any leakage of the HFA propellant occurs from thepressurized container; and wherein the package has a permeability to HFAp227 that is less than or equal to about 0.25 cc of HFA p227 per squaremeter of package per day at about 1 bar pressure and about roomtemperature, or a permeability to HFA 134a that is less than or equal toabout 4.1 cc of HFA 134a per square meter of package per day at about 1bar pressure and about room temperature.
 58. A pharmaceutical productaccording to claim 57, wherein the package has a permeability to HFAp227 that is less than or equal to about 0.15 cc of HFA p227 per squaremeter of package per day at about 1 bar pressure and about roomtemperature.
 59. A pharmaceutical product according to claim 57, whereinthe package has a permeability to HFA p227 that is less than or equal toabout 0.10 cc of HFA p227 per square meter of package per day at about 1bar pressure and about room temperature.
 60. A pharmaceutical productaccording to claim 57, wherein the package has a permeability to HFAp227 that is less than or equal to about 0.05 cc of HFA p227 per squaremeter of package per day at about 1 bar pressure and about roomtemperature.
 61. A pharmaceutical product according to claim 57, whereinthe package has a permeability to HFA 134a that is less than or equal toabout 3.5 cc of HFA 134a per square meter of package per day at about 1bar pressure and about room temperature.
 62. A pharmaceutical productaccording to claim 57, wherein the package has a permeability to HFA134a that is less than or equal to about 2.5 cc of HFA 134a per squaremeter of package per day at about 1 bar pressure and about roomtemperature.
 63. A pharmaceutical product according to claim 57, whereinthe package has a permeability to HFA 134a that is less than or equal toabout 1.5 cc of HFA 134a per square meter of package per day at about 1bar pressure and about room temperature.
 64. A pharmaceutical productaccording to claim 57, wherein the package has a permeability to HFA134a that is less than or equal to about 1.0 cc of HFA 134a per squaremeter of package per day at about 1 bar pressure and about roomtemperature.
 65. A pharmaceutical product according to claim 57, whereinthe package has a permeability to HFA 134a that is less than or equal toabout 0.5 cc of HFA 134a per square meter of package per day at about 1bar pressure and about room temperature.
 66. A pharmaceutical productaccording to claim 57, wherein the drug is selected from the groupconsisting of bronchodilators, antihistamines, lung surfactants,antiviral agents, corticosteroids, ant-inflammatory agents,anti-cholinergics, and antibiotics.
 67. A pharmaceutical productaccording to claim 57, wherein the pressurized MDI (metered doseinhaler) container further comprises one or more excipients selectedfrom the group consisting of surfactants, preservatives, flavorings,antioxidants, anti-aggregating agents and co-solvents.
 68. Apharmaceutical product according to claim 57, wherein the HFA propellantis HFA 134a.
 69. A pharmaceutical product according to claim 57, whereinthe HFA propellant is HFA p227.
 70. A pharmaceutical product accordingto claim 57, wherein the HFA adsorbent material is capable of adsorbingthe HFA propellant up to about 25% of the weight of the adsorbent.
 71. Apharmaceutical product according to claim 57, wherein the HFA gasadsorbent material is capable of adsorbing the HFA propellant up toabout 20% of the weight of the adsorbent.
 72. A pharmaceutical productaccording to claim 57, wherein the HFA adsorbent material comprisesmaterial selected from the group consisting of molecular sieves,activated clays, activated alumina, silica, zeolites, bauxites, andmixtures thereof.
 73. A pharmaceutical product according to claim 57,wherein the package is made of metal, glass, or plastic, and is selectedfrom the group consisting of bottles, bags, drum boxes, and irregularlyshaped containers.
 74. A pharmaceutical product according to claim 73,wherein the package is made of plastic.
 75. A pharmaceutical productaccording to claim 74, wherein the plastic is a flexible laminate havinga barrier layer providing said package with permeability to HFA 134aand/or HFA p227.
 76. A pharmaceutical product according to claim 75,wherein said flexible laminate has three layers:polyester/aluminum/polyethylene, wherein the aluminum layer is betweenthe polyester and polyethylene layers.
 77. A pharmaceutical productaccording to claim 75, wherein said barrier layer is made of aluminumfoil.
 78. A pharmaceutical product according to claim 57, wherein thesealed package is hermetically sealed by heat-sealing, gluing, welding,brazing, mechanical closures or clamps, or compression.